Announcement TypeThis is a reissue with modifications of RFA-HL-04-022, which was previously released September 20, 2004.

NOTICE: Applications submitted in response to this Funding Opportunity
Announcement (FOA) for Federal assistance must be submitted electronically
through Grants.gov (http://www.grants.gov)
using the SF424 Research and Related (R&R) forms and the SF424 (R&R)
Application Guide.

APPLICATIONS MAY NOT BE SUBMITTED IN PAPER FORMAT.

This FOA must be read in conjunction with the application
guidelines included with this announcement in Grants.gov/Apply for Grants (hereafter
called Grants.gov/Apply).

A registration process is necessary before submission,
and applicants are highly encouraged to start the process at least four weeks
prior to the grant submission date. See Section IV.

The purpose of this FOA is to solicit applications to develop
and validate new and innovative engineering approaches to address clinical
problems related to energy balance, intake, and expenditure. Novel sensors,
devices, imaging, and other technologies, including technologies to detect
biochemical markers of energy balance, are expected to be developed and evaluated
by collaborating engineers, physical scientists, mathematicians, and scientists
from other relevant disciplines with expertise in obesity and nutrition.
Basic and applied scientific applications with rigorous hypothesis-testing
designs or for design-directed research are encouraged. The goal is to increase
the number of useful technologies and tools available to scientists to facilitate
their research in energy balance and health. Eventually these research tools
should facilitate therapeutic advances and behavioral changes to address such
problems as weight control and obesity.

The participating organizations
intend to commit a total of $3,050,000 in FY 2007 to this FOA for payment of applications
responsive to this announcement.

The anticipated number
of awards: 10-15

Awards issued under this FOA
are contingent upon the availability of funds and the submission of a sufficient
number of meritorious applications.

Because the nature and scope of the proposed research
will vary from application to application, it is anticipated that the size
and duration of each award will also vary. The total amount awarded and
the number of awards will depend upon the mechanism numbers, quality, duration,
and costs of the applications received.

Budget and Project Period:The total project period
for an application submitted in response to this funding opportunity may
not exceed three years. Direct costs are limited to $450,000 over a three-year
period, with no more than $150,000 in direct costs allowed in any single
year.

Eligible Organizations:For-profit organizations; non-profit organizations;
public or private institutions, such as universities, colleges, hospitals,
and laboratories; units of state and local governments; eligible agencies
of the Federal government; domestic or foreign institutions/organizations;
faith-based or community-based organizations; Indian/Native American Tribal Government (Federally Recognized); Indian/Native
American Tribal Government (Other than Federally Recognized); and Indian/Native
American Tribally Designated Organization.

Eligible Project Directors/Principal Investigators
(PDs/PIs): Individuals with the skills, knowledge, and resources necessary to carry
out the proposed research are invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always encouraged
to apply for NIH support.

Applicants may submit more than one application, provided
each application is scientifically distinct.

See Section IV.1 for application materials. The SF424
(R&R) Application Guide for this FOA is located at these Web sites:

The purpose of this FOA is to solicit applications to develop and validate new
and innovative engineering approaches to address clinical problems related
to energy balance, intake, and expenditure. Novel sensors, devices, imaging,
and other technologies, including technologies to detect biochemical markers
of energy balance are expected to be developed and evaluated by collaborating
engineers, physical scientists, mathematicians, and scientists from other
relevant disciplines with expertise in obesity and nutrition. Basic and applied
scientific applications with rigorous hypothesis-testing designs or for design-directed
research are encouraged. The goal is to increase the number of useful technologies
and tools available to scientists to facilitate their research in energy balance
and health. Eventually these research tools should facilitate therapeutic
advances and behavioral changes to address such problems as weight control
and obesity.

Background

Public Health Need

Obesity is a problem of energy
balance, wherein adipose tissue stores accumulate to excess levels when expenditure
does not keep up with intake. At present, approximately 65% of American adults
are either overweight (=25 kg/m2) or obese (=30 kg/m2), and approximately 15% of American children are similarly
categorized (by age-adjusted percentiles of weight for height). This situation
reflects the high-energy efficiency of American life, where little physical
effort is needed for work and recreation, and where the national diet is abundant
in low-cost, energy-dense food. Popular approaches to weight control have
been generally unsuccessful, despite constant publicity about the problem
and considerable individual efforts at weight loss.

The health consequences of
obesity (e.g., diabetes, cancer, heart disease) are predicted to grow worse.
Type 2 diabetes rates are rising in adults and children, and a substantial
increase in morbidity and mortality from cardiovascular disease is expected.
Furthermore, obesity has been linked to the development of several types of
cancer. Ultimately, resolution of the obesity epidemic at the population
level will depend on individual behavioral change that takes place within
the larger societal environment. Such changes may be facilitated through
better medical therapies. However, technologies and tools to more easily
monitor behavior and achieve treatment goals are also needed.

Conversely, inadvertent weight
loss (cachexia) is also of high concern, particularly in the aging population.
Cachexia represents a situation of persistent negative energy balance that
often is accompanied by disproportionate loss of muscle tissue, weakness,
and steady deterioration of physical function. Aged individuals are less
likely than younger persons to be able to restore body weight after a period
of impaired intake, perhaps due to aging-related blunting of compensatory
effects on appetite. Overall, little is known about how best to reverse cachexia
once it develops; methods for detecting the onset of such periods would be
useful. Cachectic states also are common among patients with advanced stages
of chronic diseases such as heart failure, chronic obstructive pulmonary disease,
and cancer.

Aging poses additional interesting
questions related to energy balance and its assessment. When studying these,
one must distinguish between the normal biology of aging, as opposed to age-associated
ailments that are part of the health and social experience of the aged population.
Even relatively healthy, high-functioning individuals will experience age-related
declines in metabolic rate, muscle mass, energy intake, and energy expenditure.
However, many aged individuals are characterized by existing poor function,
an ever-increasing propensity to adverse unpredictable events (such as falls
and sudden illness), and impaired response to such events. Prediction of
the propensity to such events, and detection of early stages of impaired adaptive
responses, is needed in order to preserve functional capacity.

Clearly, the ability to measure
states of energy balance and its various components, such as dietary intake,
resting metabolism, and physical activity, is a critical public health need.
However, this is remarkably difficult to achieve in satisfactory fashion,
and the inconvenience, expense, and relative inaccuracy of current methods
are a persistent and serious barrier to progress. Engineering approaches
have the potential to overcome these limitations, but represent a relatively
untapped area of scientific expertise for tackling the research issues and
practical aspects of the obesity epidemic. Emerging technologies, such as
nanotechnology, also offer unique opportunities for interfacing with engineering
approaches to help address some of the problems in obesity research.

The Engineering Approach

The research proposed in
response to this FOA is expected to follow an engineering approach to substantially
address the problems of measuring and assessing energy balance to better understand,
treat, and prevent obesity. The “Engineering Approach” is a powerful method
which involves the application of knowledge of physical and biological sciences
and mathematics to address specific practical problems, in this case energy
balance and obesity. The approach incorporates the following elements in a
systematic way:

System Identification
—a clear identification of the system under investigation, its boundaries
and its interactions with neighboring systems. In the present context,
a system may be identified at the molecular, cellular, organ, or whole body
levels.

Empirical Understanding of Behavior and Response—understanding
gained from careful experiments designed to elucidate the behavior of the
system in response to internal or external stimuli, such as by interaction
with other systems.

Modeling of Physics—development of mathematical
models of the physical phenomena taking place within the system. In the present
context, one example is the development of models for physico-chemical interactions
that result in exchange of mass and energy between the system and its surroundings.

Simulation of Physical Behavior—integration
of mathematical models into simulation tools that perform rapid and efficient
solution of the governing physical models, allowing prediction of the behavior
or response of the system. Real time simulators can be used for real time
feedback and control scenarios.

Experimental Validation—comparing the measured
behavior or response of an experimental phantom or subject system to the predicted
behavior as obtained by simulation. This is a necessary step for developing
confidence in the underlying models. No simulator can be certified for use
without appropriate validation.

As illustrated by these elements,
the Engineering Approach offers the capability to create physics-based mathematical
models and validated physical simulations based on empirical evidence which
can ultimately be applied to design useful devices and processes.

Challenges in Measuring
Energy Balance

Assessment of human energy
balance, the net difference between energy intake (by diet) and expenditure
(by work and heat), is a key component of obesity research, prevention, and
treatment. The importance of accurate measurement of states of energy balance
can be appreciated by considering average weight gain in middle-aged adults
(~10 lb/decade). This significant gain in weight results from very small,
persistent excesses of intake over expenditure of approximately 0.3% of the
daily calorie consumption. This imbalance is well below the level of perception
for most individuals. Similarly, energy expenditure from physical activity
must be quantified accurately in order to understand the dose effects of exercise
on body weight and other aspects of health, such as blood pressure. Weight
loss programs often include ~5% increments of expenditure and ~20% decrements
of intake. Research on the degree of increased activity or dietary changes
that include energy reduction necessary for weight loss suggests that objective
measurable differences can be undetectable, even if reported behavior varies
between groups. At present, apart from body weight, objective measures of
achievement of behavioral goals related to weight control are difficult.

To overcome the limitations
of current methods to assess energy balance and control weight, innovative
effective approaches are needed. The problems associated with measuring and
monitoring components of human energy balance present unique opportunities
for engineers and physical scientists with expertise in the disciplines of
thermodynamics, mechanics, heat transfer, instrumentation, imaging, and design.
By collaborating with obesity researchers, such engineers and scientists may
develop the novel approaches to successfully address the problem of obesity.

Each component of the energy
balance equation presents unique challenges. For example, the difficulty
of ascertaining food intake with acceptable levels of accuracy is well known
to nutritionists. The standard self-report questionnaire and recall techniques
can provide valuable data on dietary patterns, and have been improved by electronic
information technologies and by judicious use of results from cognitive process
research. Nevertheless, these techniques are time-consuming and inconvenient.
Furthermore, considerable under-reporting of total energy intake is typical,
with this error more severe in overweight than non-overweight individuals.
At the other extreme of precision and cost is the research technique (also
occasionally used in therapeutic situations) of providing a controlled diet
with all food intake observed and defined by chemical analysis. Use of these
techniques is severely limited by their high cost and limited applicability
because of the population samples typically enrolled and the highly controlled
conditions used. Therefore, new and improved methods of determining energy
intake are critically needed for research as well as practical purposes.

Measuring the various modes
of physical activity is difficult as well, particularly outside the laboratory.
Devices must be convenient, cost-effective, suitable for short-term and habitual
activity, and valid for an array of circumstances and states of health and
fitness. None of the available methods (pedometers, accelerometers, electronic
load transducers, foot contact time monitors, heart rate monitoring) is fully
satisfactory, because they only capture a fraction of needed information.
They do not yield data that are easily understood, particularly by the lay
public, nor can they easily detect changes in behavior, except for the pedometer,
which yields data in terms of steps and can foster behavior change (i.e.,
more walking). In addition, the data yielded by these devices do not readily
translate into calories expended over the entire course of a day, which must
be compared with energy from food intake to obtain an estimate of energy balance.
Therefore, there is a problem of inter-converting measurements of energy expenditure
and intake into the same units as food intake.

Assessment of states of total
energy balance also is a critical research need. Recently improved research
tools include small or portable indirect calorimeters for short-term expenditure
measurements during physical tasks, room calorimeters with floor mounted force
plates to study movement energetics, and global positioning system (GPS) transponders
to track outdoor activity patterns. Doubly-labeled water is valuable for
determining total expenditure but is expensive, involves stable isotopes,
and only is suitable for basic research. Nevertheless, we need to be able
to accurately, precisely, and directly measure whether an individual is in
energy balance, deficit, or excess, and to translate the results into everyday
behavior. The overall state of body energy stores also cannot be easily ascertained,
particularly at the individual level, because data outputs are usually based
on group-derived algorithms. However, there has been some recent progress
in techniques used to estimate energy stores (e.g., bioelectric impedance
for percent body fat, MRI-quantified adipose depots to define metabolically
active compartments).

Such imaging and sensor technologies
will also be beneficial to the elderly. In this population, such tools are
needed to assess rates of change in total energy intake, balance, and expenditure,
and in the size and function of multiple metabolic compartments (especially
muscle mass), over relatively long intervals and in response to rare but cumulative
events. These technologies need to be able to distinguish between changes
related to the physiological process of aging, as opposed to age-associated
ailments and other changes reflecting the health and social experience of
the aged population. Any methodology used for the elderly population must
accommodate a spectrum of functioning ranging from the unusually fit, to typical
level, to the frail. Also, the information gathered should be translatable
to research and/or practical applications related to preservation or impairment
of ability to undertake activities of daily living. Assessment techniques
and data analysis methods need to be able to distinguish between true capacity
vs. elicited performance; these are highly variable among the aged, and are
unusually susceptible to measurement biases and errors. Human factors issues
are particularly important for the elderly population, and must acknowledge
participant burdens related to time (including that of caregivers/assistants),
transportation, cognitive capacity and effort, discomfort, and physical capabilities
(such as vision, hearing, strength, mobility).

In conclusion, most techniques
for measuring either side of the energy equation are costly, cumbersome, and
suitable primarily for research use. They do not address the critical issue
of overall energy balance, nor do they take advantage of new knowledge of
biochemical markers. Moreover, the available devices are not sufficiently
precise or specific for guiding individual behavior, and their measurement
errors may be greater than the treatment effect. Devices designed for use
by the public are particularly hampered by these problems. At present, we
do not have the equivalent of a "magic wristwatch" that can readily
convey whether the wearer has exceeded an intake goal or fallen short on expenditure.
New approaches might provide accurate, convenient, easily understood, and
inexpensive devices to foster research and improve clinical management of
adults and children.

The greatest scientific need
is for improved ways to achieve short- and long-term measurement of total
energy intake, expenditure, exchange, and balance, and components thereof
(e.g., resting and basal metabolic rate, physical activity, thermic effect
of food) under various physiologic conditions and activities, including work,
sleep, and leisure activity, and related body composition and metabolic compartments.
The use of micro-electro-mechanical systems for biomedical applications (BioMEMs)
to measure appropriate biomarkers of energy balance may be of great benefit
to assessing energy balance. Since many materials exhibit novel and unique
properties at the nano level, their use might represent a new approach for
precise measurements of energy status and metabolic activity.

Summary of Priority Areas

In summary, the objective
of this FOA
is to encourage and enable teams of engineers and scientists to develop and
evaluate new technologies, instrumentation, and medical devices to better
assess appropriate biomedical parameters and provide feedback and/or therapy
to reduce the prevalence of obesity and overweight. Development of new technologies
and application of existing technologies may be proposed. Examples of relevant
technologies include, but are not limited to, imaging, diagnostic and therapeutic
devices, direct and remote sensors, meters, micro-transmitters, and biomaterials.
Studies may include use of animal models and/or human participants, but are
not required to do so. If appropriate, plans for manufacturing and clinical
evaluation of developed instrumentation and medical devices should be included
in the application.

Basic and applied scientific
applications with rigorous hypothesis-testing designs or for design-directed
research are encouraged.

All grant applications submitted in response to this FOA should include sample size and statistical power calculations
appropriate to the proposed study design.

Appropriate topics for research,
development, and/or validation under this FOA include, but are not limited to, the following:

Diagnostic and therapeutic
systems to monitor energy balance and appropriate biomarkers. Such systems
may be used to provide appropriate feedback to stimulate behavior change
or to administer appropriate agents.

Biosensors, including intra- and extra-cellular
systems, for measuring calorie consumption and energy expenditure. Sensors
which are non-invasive, minimally invasive, miniature, stable, and durable.

Mathematical and computational models for
predicting interrelationships between energy balance and weight control or
obesity.

Implantable devices for
monitoring and treating obesity and overweight.

Engineering tools that integrate self-reported
information with biologic and/or sensor measures of physical activity, diet/nutrition,
and energy balance/obesity. This would include tools that measure this integrated
information in real-time.

Methodologies for imaging structure and function,
blood flow, perfusion, and metabolism from the molecular/cellular to whole
organs for the purpose of measuring and studying energy balance, intake and
expenditure, and weight control.

Identification of new and accurate biomarkers
that correlate with energy expenditure, calorie intake, physical activity,
or total energy balance, and sensors to detect levels of these biomarkers,
inasmuch as output from such sensors would provide needed feedback measures.

Special Requirements

All grant applications submitted
in response to this FOA should include sample size and statistical power calculations
appropriate to the proposed study design.

Exclusions

Certain types of investigations,
although potentially of scientific interest, will not be considered for support
by this program.

Applications proposing the
following types of studies will be considered non-responsive to the FOA:

Devices and technologies
related to the performance of bariatric surgery.

Basic investigations of cellular biochemistry
and physiology of obesity.

Studies in which the primary focus is efficacy
of behavioral, surgical, or pharmacologic treatment of obesity.

This Funding Opportunity Announcement (FOA) will use the Exploratory/Developmental
Research Grant (R21) award mechanism. The applicant will be solely responsible
for planning, directing, and executing the proposed project. This FOA uses
“Just-in-Time” information concepts.

2. Funds Available

Because the nature and scope of the proposed research will vary from application
to application, it is anticipated that the size and duration of each award
will also vary. Although the financial plans of the Institutes and Centers
(ICs) provide support for this program, awards pursuant to this funding opportunity
are contingent upon the availability of funds and the submission of a sufficient
number of meritorious applications.

The total project period for an application submitted
in response to this funding opportunity may not exceed 3 years. Although the
size of award may vary with the scope of research proposed, it is expected
that applications will stay within the budgetary guidelines for an exploratory/developmental
project. Direct costs are limited to $450,000 over a three-year period, with
no more than $150,000 in direct costs allowed in any single year.

NIH grants policies as described in the NOT-OD-05-004,
November 2, 2004.

Section III. Eligibility Information

1. Eligible Applicants

1.A. Eligible Institutions You may submit an application(s) if your organization
has any of the following characteristics:

For-profit organizations

Non-profit organizations

Public or private institutions, such as universities, colleges, hospitals,
and laboratories

Units of state government

Units of local government

Eligible agencies of the federal government

Domestic institutions/organizations

Foreign institutions/organizations

Faith-based or community-based organizations

Indian/Native American Tribal Government (Federally Recognized)

Indian/Native American Tribal Government (Other than Federally Recognized)

Indian/Native American Tribally Designated Organizations

1.B. Eligible Individuals

Any individual with the skills,
knowledge, and resources necessary to carry out the proposed research as the
Project Director/Principal Investigator (PD/PI) is invited to work with his/her
organization to develop an application for support. Individuals from underrepresented
racial and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicants may submit more
than one application, provided each application is scientifically distinct.

Section IV.
Application and Submission Information

To download a SF424 (R&R) Application Package and SF424
(R&R) Application Guide for completing the SF424 (R&R) forms for this
FOA, link to http://www.grants.gov/Apply/
and follow the directions provided on that Web site.

A one-time registration is required for institutions/organizations at both:

The individual designated as the PD/PI on the application
must also be registered in the NIH eRA Commons. It is not necessary for
PDs/PIs to register with Grants.gov.

The PD/PI must hold a PD/PI account in the Commons and
must be affiliated with the applicant organization. This account cannot
have any other role attached to it other than the PD/PI.

This registration/affiliation must be done by the Authorized
Organization Representative/Signing Official (ARO/SO) or their designee
who is already registered in the Commons.

Both the PD/PI and AOR/SO need separate accounts in
the NIH eRA Commons since both are authorized to view the application image.

Note that if a PD/PI is also an NIH peer-reviewer with
an Individual DUNS and CCR registration, that particular DUNS number and CCR
registration are for the individual reviewer only. These are different than
any DUNS number and CCR registration used by an applicant organization. Individual
DUNS and CCR registration should be used only for the purposes of personal
reimbursement and should not be used on any grant applications submitted to
the federal government.

Several of the steps of the registration process could
take four weeks or more. Therefore, applicants should immediately check with
their business official to determine whether their organization/institution
is already registered in both Grants.gov
and the Commons. The NIH
will accept electronic applications only from organizations that have completed
all necessary registrations.

1. Request Application Information

Applicants must download the SF424 (R&R) application
forms and SF424 (R&R) Application Guide for this FOA through Grants.gov/Apply.

Note: Only the forms package directly
attached to a specific FOA can be used. You will not be able to use any other
SF424 (R&R) forms (e.g., sample forms, forms from another FOA), although
some of the "Attachment" files may be useable for more than one
FOA.

Prepare all applications using the SF424 (R&R) application
forms and in accordance with the SF424 (R&R) Application
Guide (MS
Word or PDF).

The SF424 (R&R) Application Guide is critical to submitting
a complete and accurate application to NIH. There are fields within the SF424
(R&R) application components that, although not marked as mandatory, are
required by NIH (e.g., the “Credential” log-in field of the “Research &
Related Senior/Key Person Profile” component must contain the PD/PI’s assigned
eRA Commons User ID). Agency-specific instructions for such fields are
clearly identified in the Application Guide. For additional information, see
“Frequently Asked Questions – Application Guide, Electronic
Submission of Grant Applications.”

The SF424 (R&R) application is comprised of data arranged
in separate components. Some components are required, others are optional.
The forms package associated with this FOA in Grants.gov/APPLYwill include all applicable
components, required and optional. A completed application in response to
this FOA will include the following components:

Note: While both budget components are included in the
SF424 (R&R) forms package, this NIH R21
uses ONLY the detailed Research & Related Budget. (Do not use the
PHS 398 Modular Budget.)

Foreign Organizations

Several special provisions apply to applications submitted
by foreign organizations:

Charge back of customs and import fees is not allowed.

Format: Every effort should be made to comply with the
format specifications, which are based upon a standard U.S. paper size of
8.5” x 11” within each PDF.

Funds for up to 8% administrative costs (excluding equipment)
may be requested. See NOT-OD-01-028,
March 29, 2001.

Organizations must comply with federal/NIH policies
on human subjects, animals, and biohazards.

Organizations must comply with federal/NIH biosafety
and biosecurity regulations. See Section VI.2., “Administrative and National Policy
Requirements.”

Proposed research should provide special opportunities
for furthering research programs through the use of unusual talent, resources,
populations, or environmental conditions in other countries that are not readily
available in the United States or that augment existing U.S. resources.

Prospective applicants are asked
to submit a letter of intent that includes the following information:

Descriptive title of proposed research

Name, address, and telephone number of the PD/PI

Names of other key personnel

Participating institutions

Number and title of this funding opportunity

Although a letter of intent is not required, is not
binding, and does not enter into the review of a subsequent application, the
information that it contains allows IC staff to estimate the potential review
workload and plan the review.

To submit an application in response to this FOA, applicants should access
this FOA via http://www.grants.gov/Apply
and follow steps 1-4. Note: Applications must only be submitted electronically.
PAPER APPLICATIONS WILL NOT BE ACCEPTED.

In order to expedite the review, applicants are requested
to notify the NHLBIReferral
Office by email NHLBIchiefreviewbranch@nhlbi.nih.govwhen the application has been submitted. Please
include the FOA number and title, PD/PI name, and title of the application.

3.C. Application
Processing

Applications may be submitted on or after
the opening date and must be successfully received by Grants.gov no
later than 5:00 p.m. local time (of the applicant
institution/organization) on the application
submission/receipt date(s). (See Section IV.3.A. for all dates.) If an application
is not submitted by the receipt date(s) and time, the application may be delayed
in the review process or not reviewed.

Once an application package has been successfully
submitted through Grants.gov, any errors have been addressed, and the assembled
application has been created in the eRA Commons, the PD/PI and the Authorized
Organization Representative/Signing Official (AOR/SO) have two business days
to view the application image.

If everything is acceptable, no
further action is necessary. The application will automatically move forward
for processing by the Division of Receipt and Referral, Center for Scientific
Review, NIH, after two business days.

Prior to the submission deadline, the AOR/SO can
“Reject” the assembled application and submit a changed/corrected application
within the two day viewing window. This option should be used if the AOR/SO
determines that warnings should be addressed. Reminder: warnings do not stop
further application processing. If an application submission results in warnings
(but no errors) it will automatically move forward after two business days
if no action is taken. Please remember that some warnings may not be applicable
or may need to be addressed after application submission.

If the two day window falls after the submission
deadline, the AOR/SO will have the option to “Reject” the application if,
due to an eRA Commons or Grants.gov system issue, the application does not
correctly reflect the submitted application package (e.g., some part of the
application was lost or didn’t transfer correctly during the submission process).
The AOR/SO should first contact the eRA Commons Helpdesk to confirm the
system error, document the issue, and determine the best course of action.
NIH will not penalize the applicant for an eRA Commons or Grants.gov system
issue.

If the AOR/SO chooses to “Reject” the image after
the submission deadline for a reason other than an eRA Commons or Grants.gov
system failure, a changed/corrected application still can be submitted but
it will be subject to the NIH
late policy guidelines and may not be accepted. The reason for this delay
should be explained in the cover letter attachment.

Both the AOR/SO and PD/PI will receive e-mail notifications
when the application is rejected or the application automatically moves forward
in the process after two days.

Upon receipt, applications will
be evaluated for completeness by the Center for Scientific Review, NIH. Incomplete
applications will not be reviewed.

There will be an acknowledgement
of receipt of applications from Grants.gov and the Commons. Information related to the assignment
of an application to a Scientific Review Group is also in the Commons.

The NIH will not accept any application
in response to this funding opportunity that is essentially the same as one
currently pending initial review, unless the applicant withdraws the pending
application. However, when a previously unfunded application, originally submitted
as an investigator-initiated application, is to be submitted in response to
a funding opportunity, it is to be prepared as a NEW application. That is,
the application for the funding opportunity must not include an Introduction
describing the changes and improvements made, and the text must not be marked
to indicate the changes from the previous unfunded version of the application.

All NIH awards are subject to the terms and conditions,
cost principles, and other considerations described in the NIH
Grants Policy Statement.

Pre-Award Costs are allowable.
A grantee may, at its own risk and without NIH prior approval, incur obligations
and expenditures to cover costs up to 90 days before the beginning date of
the initial budget period of a new award if such costs are necessary to conduct
the project, and would be allowable under the grant, if awarded, without NIH
prior approval. If specific expenditures would otherwise require prior approval,
the grantee must obtain NIH approval before incurring the cost. NIH prior
approval is required for any costs to be incurred more than 90 days before
the beginning date of the initial budget period of a new award.

The incurrence of pre-award costs in anticipation
of a competing or non-competing award imposes no obligation on NIH either
to make the award or to increase the amount of the approved budget if an award
is made for less than the amount anticipated and is inadequate to cover the
pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award
costs result in borrowing against future support and that such borrowing must
not impair the grantee's ability to accomplish the project objectives in the
approved time frame or in any way adversely affect the conduct of the project.
See the NIH Grants
Policy Statement.

6. Other Submission Requirements

All applications are expected
to include in the Background and Significance section of the Research
Plan component a section specifically labeled “Broader Impact” and addressing
the Broader Impact merit review criterion described below in Section V.2 (Application
Review Information – Review and Selection Process). Please see examples at: http://www.nsf.gov/publications/pub_summ.jsp?ods_key=gpg

All applications are expected
to include statistical power and sample size calculations as appropriate to
the study design and the research questions under investigation.

All application budgets
should include funds for the Principal Investigator to attend an annual grantees’
meeting in the Washington DC area.

The NIH requires the PD/PI to fill
in his/her Commons User ID in the “PROFILE – Project Director/Principal Investigator”
section, “Credential” log-in field of the “Research & Related Senior/Key
Person Profile” component. The applicant organization must include its DUNS
number in its Organization Profile in the eRA Commons. This DUNS number must
match the DUNS number provided at CCR registration with Grants.gov. For additional
information, see “Registration FAQs – Important Tips -- Electronic Submission
of Grant Applications.”

Warning: Please be sure that you observe the direct
cost, project period, and page number limitations specified above for this
FOA. Application processing may be delayed or the application may be rejected
if it does not comply with these requirements.

Research Plan Component Sections

Whileeach section of the Research Plan needs to be uploaded separately
as a PDF attachment, applicants are encouraged to construct the Research Plan
as a single document, separating sections into distinct PDF attachments just
before uploading the files. This approach will enable applicants to better
monitor formatting requirements such as page limits. All attachments must
be provided to NIH in PDF format, filenames must be included with no spaces
or special characters, and a .pdf extension must be used.

Application Characteristics

All application instructions outlined
in the SF424 (R&R) application are to be followed, with the following
requirements for R21 applications:

Items 2-5 of the Research Plan
of the R21 application may not exceed 15 pages, including tables, graphs,
figures, diagrams, and charts

Preliminary data are not required but may be included
if available.

Note: While each section of the
Research Plan needs to be uploaded separately as a PDF attachment, applicants
are encouraged to construct the Research Plan as a single document, separating
sections into distinct PDF attachments just before uploading the files. This
approach will enable applicants to better monitor formatting requirements
such as page limits. All attachments must be provided to NIH in PDF format,
filenames must be included with no spaces or special characters, and a .pdf
extension must be used.

Appendix Materials

The following additional materials may be included in
the Appendix:

Up to five publications,
manuscripts (accepted for publication), abstracts, patents, or other
printed materials directly relevant to the proposed project. Do not include
manuscripts submitted for publication.

Publications in press: Include only a
publication list with a link to the on-line journal article or the NIH
PubMed Central (PMC) submission identification number. Do not include
the entire article.

Manuscripts accepted for publication but not yet
published: The entire article may be submitted electronically as a PDF attachment.

Manuscripts published but an online journal link is not available: The entire article may be submitted electronically as a PDF attachment.

Graphic images of gels, micrographs, etc. provided that the image (may be
reduced in size) is also included within the (stated) page limit of Items
2-5 of the Research Plan. No images may be included in the Appendix that
are not also represented within the Research Plan.

Do not use the Appendix to circumvent the page limitations
of the Research Plan. An application that does not observe the relevant policies
and procedures may be delayed in the review process.

Plan for Sharing Research Data

The precise content of the data-sharing plan will vary, depending on the data
being collected and how the investigator is planning to share the data. Applicants
who are planning to share data may wish to describe briefly the expected schedule
for data sharing, the format of the final dataset, the documentation to be
provided, whether or not any analytic tools also will be provided, whether
or not a data-sharing agreement will be required and, if so, a brief description
of such an agreement (including the criteria for deciding who can receive
the data and whether or not any conditions will be placed on their use), and
the mode of data sharing (e.g., under their own auspices by mailing a disk
or posting data on their institutional or personal website, through a data
archive or enclave). Investigators choosing to share under their own auspices
may wish to enter into a data-sharing agreement. References to data sharing
may also be appropriate in other sections of the application.

The reasonableness of the data sharing plan or the rationale for not sharing
research data will be assessed by the reviewers. However, reviewers will not
factor the proposed data sharing plan into the determination of scientific
merit or the priority score.

All applicants must include a plan for sharing research
data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing.
All investigators responding to this funding opportunity should include a
description of how final research data will be shared, or explain why data
sharing is not possible.

The reasonableness of the data sharing plan or the rationale for not sharing
research data will be assessed by the reviewers. However, reviewers will not
factor the proposed data sharing plan into the determination of scientific
merit or the priority score.

Sharing Research Resources

NIH policy requires that grant
awardee recipients make unique research resources readily available for research
purposes to qualified individuals within the scientific community after publication
(See the NIH Grants Policy Statementhttp://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.

The adequacy of the resources sharing plan and any
related data sharing plans will be considered by Program staff of the funding
organization when making recommendations about funding applications. The effectiveness
of the resource sharing will be evaluated as part of the administrative review
of each Non-Competing Grant
Progress Report (PHS 2590). See Section VI.3., “Reporting.”

Section V. Application
Review Information

1. Criteria

Only the review criteria described below will be
considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated
for scientific and technical merit by an appropriate peer review group convened
by the NHLBI in accordance
with the review criteria stated below.

As part of the initial merit review, all applications
will:

Undergo a selection process in which only those applications
deemed to have the highest scientific merit, generally the top half of applications
under review, will be discussed and assigned a priority score.

Receive a written critique/analysis.

Receive a second level of review by the appropriate NIH advisory council or board.

Additionally, NSF staff will
give careful consideration to the following in making funding decisions:

Integration of
Research and Education: One of the principal strategies in support of NSF's goals
is to foster integration of research and education through the programs,
projects and activities it supports at academic and research institutions.
These institutions provide abundant opportunities where individuals may
concurrently assume responsibilities as researchers, educators, and students,
and where all can engage in joint efforts that infuse education with the
excitement of discovery and enrich research through the diversity of learning
perspectives.

Integrating Diversity into NSF Programs, Projects, and Activities: Broadening opportunities and enabling the participation of all citizens,
women and men, underrepresented minorities, and persons with disabilities,
are essential to the health and vitality of science and engineering. NSF
is committed to this principle of diversity and deems it central to the
programs, projects, and activities it considers and supports.

Applications submitted in response
to this funding opportunity will compete for available funds with all other
recommended applications. The following will be considered in making funding
decisions:

Scientific merit of the proposed project as determined
by peer review

Availability of funds

Relevance to program priorities

The goals of NIH supported research
are to advance our understanding of biological systems, to improve the control
of disease, and to enhance health. In their written critiques, reviewers will
be asked to comment on each of the following criteria in order to judge the
likelihood that the proposed research will have a substantial impact on the
pursuit of these goals. Each of these criteria will be addressed and considered
in assigning the overall score, weighting them as appropriate for each application.

Significance

Approach

Innovation

Investigator

Environment

Additional Review Criteria

Note that an application does not
need to be strong in all categories to be judged likely to have major scientific
impact and thus deserve a high priority score. For example, an investigator
may propose to carry out important work that by its nature is not innovative
but is essential to move a field forward.

Significance: Does this study address an important scientific health problem?
If the aims of the application are achieved, how will scientific knowledge
or clinical practice be advanced? What will be the effect of these studies
on the concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Approach: Are the conceptual or clinical framework, design, methods,
and analyses adequately developed, well integrated, well reasoned, and appropriate
to the aims of the project? Does the applicant acknowledge potential problem
areas and consider alternative tactics?

Innovation: Is the project original and innovative? For example: Does the
project challenge existing paradigms or clinical practice; address an innovative
hypothesis or critical barrier to progress in the field? Does the project
develop or employ novel concepts, approaches, methodologies, tools, or technologies
for this area?

Investigators: Are the investigators appropriately trained and well suited
to carry out this work? Is the work proposed appropriate to the experience
level of the PD/PI and other researchers? Does the investigative team bring
complementary and integrated expertise to the project (if applicable)?

Environment: Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed studies benefit
from unique features of the scientific environment, or subject populations,
or employ useful collaborative arrangements? Is there evidence of institutional
support?

Broader Impact: What are the broader impacts of the proposed activity?
How well does the activity advance discovery and understanding while promoting
teaching, training, and learning? How well does the proposed activity broaden
the participation of underrepresented groups (e.g., gender, ethnicity, disability,
geographic, etc.)? To what extent will it enhance the infrastructure for research
and education, such as facilities, instrumentation, networks, and partnerships?
Will the results be disseminated broadly to enhance scientific and technological
understanding? What may be the benefits of the proposed activity to society?

In addition to the above criteria,
the following items will continue to be considered in the determination of
scientific merit and the priority score:

Protection of Human Subjects from Research Risk:
The involvement of human subjects and protections from research risk relating
to their participation in the proposed research will be assessed. See item
6 of the Research Plan component of the SF424 (R&R).

Inclusion of Women, Minorities and Children in Research: The
adequacy of plans to include subjects from both genders, all racial and ethnic
groups (and subgroups), and children as appropriate for the scientific goals
of the research will be assessed. Plans for the recruitment and retention
of subjects will also be evaluated. See item 7 of the Research Plan component
of the SF424 (R&R).

Care and Use of Vertebrate Animals in Research: If
vertebrate animals are to be used in the project, the five items described
under item 11 of the Research Plan component of the SF424 (R&R) will be
assessed.

2.B. Additional Review Considerations

Budget and Period of Support: The reasonableness of the proposed budget
and the appropriateness of the requested period of support in relation to
the proposed research may be assessed by the reviewers. Is the number of person
months listed for the effort of the PD/PI appropriate for the work proposed?
Is each budget category realistic and justified in terms of the aims and methods?

2.C. Sharing Research Data

The reasonableness of the data
sharing plan or the rationale for not sharing research data may be assessed
by the reviewers. However, reviewers will not factor the proposed data sharing
plan into the determination of scientific merit or the priority score. The
funding organization will be responsible for monitoring the data sharing policy.
http://grants.nih.gov/grants/policy/data_sharing.

2.D. Sharing Research Resources

NIH policy requires that grant awardee recipients
make unique research resources readily available for research purposes to
qualified individuals within the scientific community after publication (See
the NIH Grants Policy Statementhttp://grants.nih.gov/archive/grants/policy/nihgps_2003/index.htm#_Toc54600131).
Investigators responding to this funding opportunity should include a sharing
research resources plan addressing how unique research resources will be shared
or explain why sharing is not possible.

Program staff will be responsible for the administrative
review of the plan for sharing research resources.

The adequacy of the resources sharing
plan and any related data sharing plans will be considered by Program staff
of the funding organization when making recommendations about funding applications.
The effectiveness of the resource sharing will be evaluated as part of the
administrative review of each Non-Competing Grant
Progress Report (PHS 2590), See Section VI.3., “Reporting.”

Model Organism Sharing Plan: Reviewersare asked to assess
the sharing plan in an administrative note. The sharing plan itself should
be discussed after the application is scored. Whether a sharing plan is reasonable
can be determined by the reviewers on a case-by-case basis, taking into consideration
the organism, the timeline, the applicant's decision to distribute the resource
or deposit it in a repository, and other relevant considerations

3. Anticipated Announcement and Award
Dates

Not Applicable

Section VI. Award Administration
Information

1. Award Notices

After the peer review of the application is completed, the PD/PI will be able
to access his/her Summary Statement (written critique) via the NIH eRA Commons.

A formal notification in the form of a Notice of Award
(NoA) will be provided to the applicant organization. The NoA signed by the
grants management officer is the authorizing document. Once all administrative
and programmatic issues have been resolved, the NoA will be generated via
email notification from the awarding component to the grantee business official.

Selection of an application for award is not an authorization
to begin performance. Any costs incurred before receipt of the NoA are at
the recipient's risk. These costs may be reimbursed only to the extent considered
allowable pre-award costs. See Section IV.5., “Funding Restrictions.”

We encourage your inquiries concerning
this funding opportunity and welcome the opportunity to answer questions from
potential applicants. Inquiries may fall into three areas: scientific/research,
peer review, and financial or grants management issues:

Human Subjects Protection:Federal regulations (45 CFR 46) require that applications
and proposals involving human subjects must be evaluated with reference to
the risks to the subjects, the adequacy of protection against these risks,
the potential benefits of the research to the subjects and others, and the
importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:Data and safety monitoring is required for all types
of clinical trials, including physiologic toxicity and dose-finding studies
(Phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative
trials (Phase III). Monitoring should be commensurate with risk. The establishment
of data and safety monitoring boards (DSMBs) is required for multi-site clinical
trials involving interventions that entail potential risks to the participants
(“NIH Policy for Data and Safety Monitoring,” NIH Guide for Grants and
Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:Investigators should seek guidance from their institutions,
on issues related to institutional policies and local IRB rules, as well as
local, State and Federal laws and regulations, including the Privacy Rule.
Reviewers will consider the data sharing plan but will not factor the plan
into the determination of the scientific merit or the priority score.

Access to Research Data through
the Freedom of Information Act:The Office of Management and Budget (OMB) Circular
A-110 has been revised to provide access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1) first
produced in a project that is supported in whole or in part with federal funds
and (2) cited publicly and officially by a federal agency in support of an
action that has the force and effect of law (i.e., a regulation) may be accessed
through FOIA. It is important for applicants to understand the basic scope
of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this funding opportunity
in a public archive, which can provide protections for the data and manage
the distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design and
include information about this in the budget justification section of the
application. In addition, applicants should think about how to structure informed
consent statements and other human subjects procedures given the potential
for wider use of data collected under this award.

Sharing of Model Organisms:NIH is committed to support efforts that encourage
sharing of important research resources including the sharing of model organisms
for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm).
At the same time the NIH recognizes the rights of grantees and contractors
to elect and retain title to subject inventions developed with federal funding
pursuant to the Bayh Dole Act (see the NIH Grants Policy
Statement. Beginning October 1, 2004, all investigators submitting
an NIH application or contract proposal are expected to include in the application/proposal
a description of a specific plan for sharing and distributing unique model
organism research resources generated using NIH funding or state why such
sharing is restricted or not possible. This will permit other researchers
to benefit from the resources developed with public funding. The inclusion
of a model organism sharing plan is not subject to a cost threshold in any
year and is expected to be included in all applications where the development
of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:It is the policy of the NIH that women and members
of minority groups and their sub-populations must be included in all NIH-supported
clinical research projects unless a clear and compelling justification is
provided indicating that inclusion is inappropriate with respect to the health
of the subjects or the purpose of the research. This policy results from the
NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators
proposing clinical research should read the "NIH Guidelines for Inclusion
of Women and Minorities as Subjects in Clinical Research” (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.
The amended policy incorporates: the use of an NIH definition of clinical
research; updated racial and ethnic categories in compliance with the new
OMB standards; clarification of language governing NIH-defined Phase III clinical
trials consistent with the SF424 (R&R) application; and updated roles
and responsibilities of NIH staff and the extramural community. The policy
continues to require for all NIH-defined Phase III clinical trials that: (1)
all applications or proposals and/or protocols must provide a description
of plans to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable; and (2) investigators
must report annual accrual and progress in conducting analyses, as appropriate,
by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical
Research:The NIH maintains a policy that children (i.e., individuals
under the age of 21) must be included in all clinical research, conducted
or supported by the NIH, unless there are scientific and ethical reasons not
to include them.

Required Education on the Protection of Human Subject
Participants:NIH policy requires education on the protection of
human subject participants for all investigators submitting NIH applications
for research involving human subjects and individuals designated as key personnel.
The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

NIH Public Access Policy:NIH-funded investigators are requested to submit to
the NIH manuscript submission (NIHMS) system (http://www.nihms.nih.gov)
at PubMed Central (PMC) an electronic version of the author's final manuscript
upon acceptance for publication, resulting from research supported in whole
or in part with direct costs from NIH. The author's final manuscript is defined
as the final version accepted for journal publication, and includes all modifications
from the publishing peer review process.

NIH is requesting that authors submit manuscripts
resulting from (1) currently funded NIH research projects or (2) previously
supported NIH research projects if they are accepted for publication on or
after May 2, 2005. The NIH Public Access Policy applies to all research grant
and career development award mechanisms, cooperative agreements, contracts,
Institutional and Individual Ruth L. Kirschstein National Research Service
Awards, as well as NIH intramural research studies. The Policy applies to
peer-reviewed, original research publications that have been supported in
whole or in part with direct costs from NIH, but it does not apply to book
chapters, editorials, reviews, or conference proceedings. Publications resulting
from non-NIH-supported research projects should not be submitted.

For more information about the Policy or the submission
process, please visit the NIH Public Access Policy Web site at http://publicaccess.nih.gov/ and view
the Policy or other Resources and Tools, including the Authors' Manual.

Standards for Privacy of Individually Identifiable
Health Information:The Department of Health and Human Services (DHHS)
issued final modification to the "Standards for Privacy of Individually
Identifiable Health Information," the "Privacy Rule," on August
14, 2002. The Privacy Rule is a federal regulation under the Health Insurance
Portability and Accountability Act (HIPAA) of 1996 that governs the protection
of individually identifiable health information, and is administered and enforced
by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of
the Privacy Rule reside with the researcher and his/her institution. The OCR
website (http://www.hhs.gov/ocr/) provides
information on the Privacy Rule, including a complete Regulation Text and
a set of decision tools on "Am I a covered entity?" Information
on the impact of the HIPAA Privacy Rule on NIH processes involving the review,
funding, and progress monitoring of grants, cooperative agreements, and research
contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.

URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within
specified page limitations. For publications listed in the appendix and/or
Progress report, internet addresses (URLs) must be used for publicly
accessible on-line journal articles. Unless otherwise specified in this
solicitation, Internet addresses (URLs) should not be used to provide
any other information necessary for the review because reviewers are
under no obligation to view the Internet sites. Furthermore, we caution reviewers
that their anonymity may be compromised when they directly access an Internet
site.

Healthy People 2010:The Public Health Service (PHS) is committed to achieving
the health promotion and disease prevention objectives of "Healthy People
2010," a PHS-led national activity for setting priority areas. This FOA
is related to one or more of the priority areas. Potential applicants may
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:

This program is described in theCatalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements
of Executive Order 12372 or Health Systems Agency review. Awards are made
under the authorization of Sections 301 and 405 of the Public Health Service
Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part
52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions,
cost principles, and other considerations described in the NIH Grants Policy
Statement.

The PHS strongly encourages all grant recipients to
provide a smoke-free workplace and discourage the use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care, or early childhood
development services are provided to children. This is consistent with the
PHS mission to protect and advance the physical and mental health of the American
people.

Loan Repayment Programs:NIH encourages applications for educational loan repayment
from qualified health professionals who have made a commitment to pursue a
research career involving clinical, pediatric, contraception, infertility,
and health disparities related areas. The LRP is an important component of
NIH's efforts to recruit and retain the next generation of researchers by
providing the means for developing a research career unfettered by the burden
of student loan debt. Note that an NIH grant is not required for eligibility
and concurrent career award and LRP applications are encouraged. The periods
of career award and LRP award may overlap providing the LRP recipient with
the required commitment of time and effort, as LRP awardees must commit at
least 50% of their time (at least 20 hours per week based on a 40 hour week)
for two years to the research. For further information, please see: http://www.lrp.nih.gov.